The overall objective of the proposed work is to map and positionally clone genes responsible for moderate to severe hearing loss. Deafness is one of the most prevalent sensory defects in humans and a majority of genetic hearing loss is recessively inherited and is the only clinical manifestation (nonsyndromic). Untreated hearing loss results in speech difficulties and often has a detrimental effect on family relations, occupation and education of these individuals and can contribute to depression. Although over 20 genes have been cloned for nonsyndromic, recessively inherited, severe-to-profound deafness, the genes responsible for recessive, moderate to severe hearing loss are largely unknown due to the scarcity of such families currently recruited in genetic linkage studies. To remove this bias, we plan to: a) Enroll large consanguineous families with recessively inherited moderate to severe hearing loss from Pakistan, b) Discover novel loci by performing genome-wide linkage analyses on the collected samples &c) Identify the causative genes by positional cloning. To achieve these aims we will recruit families with the help of audiologists, Pakistan Society for Communication Disorders, Department of Special Education and regular schools. After collection of blood samples and extraction of DNA, we will screen samples from affected individuals for shared homozygosity with markers flanking known deafness loci. If homozygosity at some of these markers segregates with the hearing loss, the appropriate genes will be sequenced in order to find mutations and determine genotype-phenotype correlations. Families in which hearing loss is negative for linkage to known loci will be selected for the identification of novel loci. Markers for genome-wide linkage analyses will be used and two-point LOD (Likelihood of Odds) scores calculated to identify the disease loci. After mapping and refining these loci, we will positionally clone the disease genes by mutational analyses of the genes in the mapped intervals. The knowledge gained by this study may provide clinical markers to assist in genetic diagnosis of hearing loss and will be useful in genetic counseling of the participants enabling them to make choices since cousin marriages are common in Pakistan. Identification of the genes underlying hearing loss due to genetic disorders will reveal the crucial molecules necessary for audition and will elucidate their normal function. This is a first step in developing treatments and cures for hearing loss in the future.